Submissions for variant NM_000784.4(CYP27A1):c.1342C>T (p.Arg448Cys)

gnomAD frequency: 0.00001  dbSNP: rs730882199

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000171331	SCV000221528	likely pathogenic	not provided		criteria provided, single submitter	research
GeneDx	RCV000171331	SCV001985472	uncertain significance	not provided	2020-06-30	criteria provided, single submitter	clinical testing	Observed in a patient with choreoathetosis, no cataracts, and normal cholestanol who underwent whole exome sequencing in published literature (Alazami et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25558065)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804890	SCV002050908	uncertain significance	not specified	2021-12-10	criteria provided, single submitter	clinical testing	Variant summary: CYP27A1 c.1342C>T (p.Arg448Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 250076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1342C>T has been reported in the literature in at-least one individual with choreoathetosis, no cataract and normal levels of cholestanol but not with features of Cerebrotendinous Xanthomatosis. These report(s) do not provide unequivocal conclusions about association of the variant with Cerebrotendinous Xanthomatosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001850285	SCV002291131	uncertain significance	Cholestanol storage disease	2022-09-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 448 of the CYP27A1 protein (p.Arg448Cys). This variant is present in population databases (rs730882199, gnomAD 0.02%). This missense change has been observed in individual(s) with developmental regression and dystonia (PMID: 25558065). ClinVar contains an entry for this variant (Variation ID: 183278). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP27A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV001850285	SCV002792398	uncertain significance	Cholestanol storage disease	2022-02-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515122	SCV003539141	uncertain significance	Inborn genetic diseases	2021-12-28	criteria provided, single submitter	clinical testing	The c.1342C>T (p.R448C) alteration is located in exon 8 (coding exon 8) of the CYP27A1 gene. This alteration results from a C to T substitution at nucleotide position 1342, causing the arginine (R) at amino acid position 448 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre	RCV000162100	SCV000196385	likely pathogenic	Regression of motor development with severe dystonia and corresponding basal ganglia lesions	2014-12-01	flagged submission	research